Immunotherapy has had unprecedented success in the clinic. However, the majority of patients treated with the immune checkpoint inhibitors (ICB) do not gain clinical benefits from these treatments. The mechanisms of resistance to ICB are not fully understood. Through comprehensive computational and follow-up experimental validations, we have found that a subset of cancers is characterized by severe defects in the RNA Polymerase II ? mediated transcription elongation, resulting in genome-wide deregulation of mRNA synthesis, splicing and processing (Transcription Elongation defect: TEdeff). TEdeff strongly affected immune-related pathways, and impaired tumor cell response to pro-inflammatory immune attacks in vitro and in vivo. As such, we found that TEdeff predicted poor response to immunotherapeutic agents in the clinic, including immune checkpoint inhibitors, in 4 different cohorts. We propose that 1) loss of transcriptional elongation functions leads to epigenetic and transcriptional defects of pro-inflammatory pathway genes, and that TEdeff can be reversed by restoring the expression of key genes. In addition, 2) we propose that TEdeff paradoxically attracts T-cells due to the activation of innate sensing pathways, but confers resistance to anti-tumor immune attack through both tumor-extrinsic (by regulating tumor-infiltrating lymphocyte function) and ?intrinsic (by regulating tumor cell signaling) mechanisms. Therefore, this proposal has a high promise of the molecular characterization of a novel major tumor phenotype, and identifying strategies for its reversal or targeting in the clinic. Given that TEdeff is observed in >25% of all cancers, this proposal is of high clinical significance.